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Effects of Zinc Exposure on Zinc Transporter Expression in Human Intestinal Cells of Varying Maturity

Jou, Ming-Yu*; Philipps, Anthony F; Kelleher, Shannon L; Lönnerdal, Bo*

Journal of Pediatric Gastroenterology & Nutrition: June 2010 - Volume 50 - Issue 6 - p 587–595
doi: 10.1097/MPG.0b013e3181d98e85
Original Articles: Gastroenterology

Objectives: Zinc (Zn) homeostasis in adults is achieved principally through a balance between intestinal absorption and excretion involving adaptive mechanisms programmed by levels of dietary Zn. Zn absorption in infants is not as tightly regulated as that in adults, which may induce potential toxicity in infants due to the relatively high capacity of Zn absorption. We hypothesized that intestinal Zn homeostasis is developmentally regulated and depends on intestinal maturation, which in turn affects Zn transporter regulation.

Materials and Methods: Cultured human fetal (FHs 74 Int, F) and adult (Caco-2: undifferentiated, U; differentiated, D) intestinal cells were used to determine developmental differences in Zn uptake and effects of Zn exposure on Zn transporters.

Results: Zn uptake rates in F and U cells were higher compared with D cells (F, 9-fold; U, 3-fold). F cells were more intolerant to Zn exposure than were U or D cells (LD50 = 67.9 ± 5.3; 117.0 ± 5.2; 224.4 ± 3.7 μmol/L, respectively). Two mechanisms were involved in developmental regulation of Zn homeostasis: differential Zn transporter expression and differential response to Zn exposure. In F cells, zinc-regulated transporter (ZRT)/iron-regulated transporter (IRT)–like protein (Zip)4 expression was undetectable; Zn (50 μmol/L) increased levels of Zn transporter (ZnT)1, ZnT2, and metallothionein-1 mRNA and ZnT1 protein. U and D cells had higher mRNA expression of ZnT1 (U: 5-fold; D: 7-fold, respectively) and ZnT2 (U: 2-fold; D: 9-fold, respectively) than F cells, and D cells also had higher Zip4 expression (3-fold) than U cells. In U cells, Zn exposure increased Zip4 protein level, but not membrane-associated abundance. However, in D cells, Zn exposure decreased both the Zip4 protein level and membrane-associated abundance.

Conclusions: Zn absorption is developmentally regulated through intestinal Zn efflux and sequestration and import mechanisms, which may be responsible for differences in Zn absorption observed between infants and adults.

*Department of Nutrition, USA

Department of Pediatrics, University of California, Davis, USA

Department of Nutritional Sciences, Pennsylvania State University, University Park, USA.

Received 8 July, 2009

Accepted 28 January, 2010

Address correspondence and reprint requests to Dr Bo Lönnerdal, Department of Nutrition, University of California, Davis, CA 95616 (e-mail:

This study was supported by the Children's Miracle Network.

The authors report no conflicts of interest.

© 2010 Lippincott Williams & Wilkins, Inc.